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Placebo Effect Linked to Dopamine-Clearing Enzyme

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Patients who carry one particular functional polymorphism of an enzyme responsible for clearing dopamine from the prefrontal cortex region of the brain are more likely to respond to placebo therapy than those with a different variant of the enzyme, as long as the placebo is administered in a caring, positive manner, researchers report. The polymorphism generates a less-active version of the enzyme catechol-O-methyltransferase (COMT), which is less efficient than the native enzyme at mopping up dopamine that has been released from nerve synapses.

Dopamine has previously been linked with placebo response in pain, Parkinson’s disease, and depression, and the prefrontal cortex—where COMT is crucial for dopamine clearance—is a brain region activated during the placebo response, report the investigators at Beth Israel Deaconess Medical Center. Given that the less-active methionine (val158met, or just "met") polymorphism of COMT has itself been linked with variations in memory function, cognition, confirmational bias, pain processing, and sensitivity, Ted J. Kaptchuk and colleagues revisited their prior clinical study on placebo response in IBS patients to see whether the COMT met polymorphism also impacted on how likely the participants were to have responded to placebo therapy.

This original study had involved three different treatment arms. Participants in one arm were not given any treatment (the "waitlist" group, which acted as a control), those in a second "limited placebo" group were treated using placebo acupuncture in a businesslike, clinical manner (i.e., with little support), while the third cohort of patients was treated using the same placebo acupuncture, but from a warm and supportive healthcare provider who expressed confidence in its effectiveness. This was the "augmented placebo" arm. The trial data showed that the cohort that received the more positively administered placebo treatment were far more likely to respond to therapy in terms of improved IBS symptoms and other measures.

To see whether there may be a genetic component to the likelihood of placebo response the Beth Deaconess have now gone back, genotyped blood samples from the patients involved in the study, and used regression analysis to marry genotype data with the type of treatment received. The results were striking, but only among patients in the augmented placebo arm. In this cohort patients who were homozygous for the met allele (met/met) showed the greatest improvements in their IBS symptoms.

In comparison, patients carrying two copies of the native "val" polymorphism (val/val) showed the least improvements, and those who were heterozygous (val/met), had an intermediate response. There was a direct, and linear relationship between the number of met alleles, and the treatment response. A much smaller met/met-associated effect was observed among patients in the limited placebo treatment cohort, and there was no effect at all in the waitlist control group.

Effectively, the data indicate that the COMT val158met allele could represent a marker for placebo responders in IBS patients at least, the investigators state. And inclusion of the control waitlist patients, who were by far the least likely to "respond" and didn’t show any link between response and COMT polymorphism, acted to support the notion that met is a true predictor of the placebo effect, and not just improvements in general.

"To our knowledge, this is the first study to demonstrate genetic modulation of true placebo effects disassociated from changes related to disease natural history and regression to the mean," they write in their published paper in PLoS One. "It is also the first study to demonstrate a relationship between different levels of placebo treatment and COMT genotype."

In fact, they point out, although a number of studies have previously looked at the placebo response, it’s the addition of a no-treatment control arm (the waitlist group in this case), and an ‘augmented’ therapy arm that has provided a clear demonstration that a genetic factor can play a role in whether patients will respond to placebo, albeit with subjective (in the case of IBS), but measurable improvements in symptoms.

"It is unlikely that a single locus like COMT fully accounts for a complex behavioral phenotype like placebo response," the team admits. "However, given that COMT val158met is a functional polymorphism, which results in a three to four-fold reduction in prefrontal dopamine, it has a greater potential to contribute to behavioral variability than other non-functional or noncoding polymorphisms." The team also points out that their findings reinforce how powerful the patient-doctor interaction can be in terms of enhancing healing. And their data indicate that genetics may play a role in whether the patient is refractory to this positive interaction. “Our findings that val/val patients are less influenced by the placebo treatment, regardless of whether it is delivered in an augmented or limited context, potentially shed some light on this clinical challenge.”

The implications for drug developers undertaking clinical trials are also evident, Dr. Kaptchuk adds. “Our study is only the first step, and our findings are preliminary, but we hope that as further research unfolds, the implications and expansion of these findings might contribute to improving both clinical care and the efficiency of conducting clinical trials.”

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